Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40–50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV + and HPV - HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV + and HPV - HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV + and HPV - HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.

Head and neck squamous cancer progression is marked by CLIC4 attenuation in tumor epithelium and reciprocal stromal upregulation of miR-142-3p, a novel post-transcriptional regulator of CLIC4

“…Thus, the miR-142-3p upregulation described in certain cancers may be due to the presence of immune cells in tissue homogenates, which can only be distinguished by single-cell sequencing or in situ analysis. This, as well as the specific immune cell types expressing miR-142-3p, should be considered in future analyses, and those ascribing biomarker function to miR-142-3p should determine if it is a tumor cell-autonomous biomarker, a general marker of inflammation, or a marker of specific tumor-associated immune cell states, the latter of which could have implications for sensitivity to immunotherapy [107].…”

Tumor immune microenvironment in head and neck cancers

“…HNSCCs can severely impact the quality of life of patients while have poor prognosis, low responsiveness to treatment, and drug resistance. HNSCC malignancy has a high morbidity and mortality rate since only 50% to 60% of patients have a survival rate of 5 years after diagnosis of HNSCC, and up to 30% of patients develop cancer relapse and treatment failure 6 . It has been found that one of the most imperative prognostic determinants of the survival rate from HNSCC is the presence of lymph node metastases 7 …”

Machine Classification of Methylomes in Cancer

“…In addition, half of the independent HNSC data set was HPV positive (HPV+). HPV+ oropharyngeal squamous cell carcinomas are very different to HPVoropharyngeal carcinomas [25], and they have distinct methylation patterns [26]. The HPV status of the TCGA data is unknown, but as HPV+ tumours are seen more frequently in the oropharynx than other tissues of origin and only a small fraction of the TCGA data is from the oropharynx, it is likely that a very small fraction of the training data was HPV+.…”